Hepatitis B virus (HBV) infection is a major health problem throughout the world. HBV is a causative agent of both an acute and chronic form of hepatitis. It is estimated that more than 200 million people worldwide are chronic carriers of HBV.
HBV belongs to the family Hepadnaviridae, which includes a number of related viruses which primarily infect small rodents. All members of the hepadnavirus family have a number of characteristics in common such as morphological appearance, antigenic makeup and DNA size and structure. Pathological findings following infection with the members of this family are quite similar. Studies show that the replication and spread of the viruses of this family are dependent upon the reverse transcriptase of an RNA intermediate.
HBV itself is a double-stranded DNA virus. Its DNA polymerase catalyzes both DNA-dependent and RNA-dependent RNA synthesis. The life cycle of HBV involves the enzyme reverse transcriptase in its DNA replication. There is presently no effective drug for the treatment of an HBV infection.
The best defense against Hepatitis B viral infection is vaccination. However, even with the advent of immunization programs, the disease remains a severe worldwide problem. Although acute Hepatitis B viral infections are generally self-limiting, in many instances the disease can progress to the chronic state. A Hepatitis B viral infection also creates a risk to fulminant hepatitis. In addition, Hepatitis B viral infections are closely associated with hepatocellular carcinoma.
Present therapy for the treatment of chronic Hepatitis B viral infections includes the administration of interferon alpha, and various nucleoside analogs such as adenine arabinoside or its monophosphate (ara-AMP). These therapeutic approaches have met with limited success. The use of AZT, acyclovir and foscarnet (in the case of fulminant hepatitis) to treat hepatitis has also been tried with little, if any, success.
Several 2',3'-dideoxynucleoside analogs have been reported in the literature to exhibit potent activity against Hepatitis B virus in culture. In particular, the nucleoside analogs (+) and (-)-2',3'-Dideoxy-3'-thiacytidine ((.+-.) SddC) have shown to be potent inhibitors of Hepatitis B virus and the (-)isomer was particularly interesting in that it exhibited relatively low toxicity along with its potent activity. The 5-fluoro analog ((.+-.)5-FSddC) was also shown to exhibit potent activity. (Chang, et al., Jour. Biol. Chem., 267, 222414, 1992 and Chang, et al., Jour. Biol. Chem., 267, 13938, 1992).
A number of 2',3'-dideoxynucleoside analogs have exhibited significant activity against human immunodeficiency virus (HIV), including 3'-deoxy-2',3'-didehydrothymidine (D4T), 2',3'-dideoxy-2',3'-didehydroguanosine (Carbovir), 2',3'-dideoxycytidine (DDC), 3'-azido-2',3'-dideoxyguanosine (AZG), 2',3'-dideoxyinosine (DDI), 2',3'-dideoxy-2',3'-didehydrocytidine, 3'-fluoro-2',3'-dideoxyadenosine, 3'-fluoro-3'-deoxythymidine and 3'-azido-2',3'-dideoxyuridine. See, Larder, et al., Antimicrob. Agents Chemother., 34, 436 (1990). Certain of these analogs, including ddC, are currently used as anti-HIV agents. Among the dideoxynucleosides, ddC has been shown to be among the most potent inhibitors of HIV.
Although research has concentrated on discovering an effective treatment protocol against HBV and certain potent anti-HBV nucleoside analogs have been synthesized and characterized, an ideal drug has not been found primarily because of the adverse effects that the present compounds elicit.
The major problem in optimizing a treatment protocol against HBV is to provide acceptable anti-HBV activity while minimizing the toxicity to the host cell as well as the anti-mitochondrial DNA effects that many present anti-HBV nucleosides exhibit.
The present invention relates to synthetic nucleosides which exhibit potent anti-viral activity (in particular, anti-HBV activity) with significantly reduced toxicity to the host cell. In contrast to the prior art compounds, the analogs of the present invention represent a viable medicinal therapeutic approach to HBV infections.